In this international multi-center trial, standard doses of acyclovir for HSV-2 suppression in HIV-1/HSV-2 dually-infected African women and men with CD4 counts ≥250 cells/mm3
reduced the risk of HIV-1 disease progression by 16% (95% CI 2–29%). We have previously reported that acyclovir reduced HIV-1 plasma RNA by 0.25 log10
copies/mL in this trial population.(19
) This result was similar to that seen in prior trials of short-term HSV-2 suppression (1 to 3 months) showing a 0.25–0.5 log10
copies/mL reduction in HIV-1 levels (summarized in ).(14
) We infer that the reduction in HIV-1 levels during acyclovir suppression mediated a reduction in risk of HIV-1 disease progression. Consistent with this hypothesis, a recent systematic review of U.S. and African observational studies found a 0.3 log10
copies/mL reduction in plasma HIV-1 levels would be predicted to reduce risk of HIV-1 progression by 25%.(31
) Our results demonstrate that a non-ART based strategy (i.e., HSV-2 suppression) that reduces plasma HIV-1 levels by a lesser amount than current combination ART regimens can modestly delay HIV-1 disease progression.
Comparison of clinical trials of HSV-2 suppression on HIV-1 plasma RNA in HSV-2/HIV-1 dually-infected persons
Early studies of zidovudine monotherapy showed similar reductions in HIV-1 plasma RNA(32
) and decreased risk of disease progression and mortality(33
) as were demonstrated in the present study. Zidovudine effects waned over 3–6 months as resistant HIV-1 variants were selected. Acyclovir is a highly HSV-specific chain terminator requiring HSV thymidine kinase for initial phosphorylation, and is preferentially incorporated by HSV DNA polymerase. This, in conjunction with the 73% reduction in the incidence of HSV-2 positive GUD among those randomized to acyclovir in our study,(19
) leads us to hypothesize that acyclovir’s effect in reducing HIV-1 levels is mediated through HSV-2 suppression. Notably, recent in vitro
studies suggest that acyclovir may directly inhibit HIV-1 replication, possibly utilizing kinases from other ubiquitous herpesviruses (e.g., human herpesvirus 6);(34
) and one in vitro
study using high-dose acyclovir demonstrated selection of an uncommon HIV-1 mutation, V75I.(35
) However, the 0.25 log10
average decreased plasma HIV-1 levels observed in our study persisted through 24 months of follow-up(19
) without an HIV-1 plasma RNA ‘rebound’ that might be expected from selection of resistant variants. Future investigations will assess incidence of HIV-1 mutations in the acyclovir versus placebo arms during follow-up to evaluate specific mechanisms underlying HIV-1 plasma RNA reductions.
Acyclovir has a much lower frequency of adverse effects than many ART regimens currently used in resource-poor settings; as previously reported, we found no serious adverse events associated with acyclovir in the present trial.(19
) High tolerability of acyclovir likely contributed to the high adherence in this study. In addition, the lack of need for specific laboratory monitoring for acyclovir toxicity during HSV-2 suppression is particularly important where laboratory infrastructure for monitoring and access to care are limited.
Our selection of a standard dose of acyclovir (comparable to valacyclovir 500 mg twice daily (36
)) was based on demonstrated efficacy in reducing frequency of symptomatic GUD and asymptomatic genital HSV-2 reactivation in HIV-1/HSV-2 dually-infected persons,(37
) well-documented safety, generic availability, and relative low cost. A meta-analysis of several small studies of high-dose HSV-2 suppression ( 3200 mg/day) in conjunction with mono- or dual-nucleoside ART identified a similar magnitude of effect on HIV-1 associated mortality (HR 0.78, 95% CI 0.65–0.93) to what we observed.(39
) Additional studies are needed to directly assess whether higher doses of herpes suppressive therapy have greater impact on HIV-1 plasma levels and disease progression.
Further study is needed to determine if HSV-2 suppression could be implemented to slow HIV-1 disease progression until HIV-1/HSV-2 dually-infected persons reach guidelines for ART initiation. presents our summary results in the context of other non-ART biomedical interventions evaluated for their effect on measures of HIV-1 disease progression. For example, trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis and multivitamins in HIV-1 infected persons have become standard practice in many resource-poor settings, based on trials showing a reduction in HIV-1 associated mortality of ~45%(40
) and 27%(43
), respectively. However, those non-ART interventions to reduce HIV-1 disease progression were conducted in the era before combination ART was widely available and thus included considerable follow-up of persons with advanced HIV-1 disease. Furthermore, subgroup analyses found that TMP-SMX had greatest efficacy among individuals with CD4 <200 cells/mm3
or symptoms of advanced immunosuppression.(40
) In contrast, we found that HSV-2 suppression delayed HIV-1 disease progression in a low-resource setting among men and women with a wide range of ages and CD4 counts ≥250 cells/mm3
at enrollment. The International AIDS Society-USA Panel recently revised recommendations to initiate ART at CD4 <350 cells/mm3
in some settings.(28
) Earlier ART initiation will likely have a greater impact on disease progression than we found with acyclovir in this study and may have an ancillary benefit of reducing HIV-1 transmission. However, currently there are insufficient resources in many settings to provide ART even to those with CD4 counts <200/mm3
) Furthermore, given the interest in identifying interventions for persons with higher CD4 counts, more detailed evaluation of HSV-2 suppression among persons with CD4 >500 is needed. A recent cost-effectiveness analysis found that HSV-2 suppression meets the World Development Report cost-effectiveness threshold ($1000 per life-year gained) at the lowest available pricing for generic acyclovir ($25 per year for twice daily acyclovir 400 mg tablets).(45
) However, the local pricing of acyclovir varies widely and can exceed the international reference price by 6 to 10-fold in subSaharan Africa.(47
) Clearly, efforts are needed to improve drug procurement, distribution and access across sub-Saharan Africa in order to maximize the impact of acyclovir on the HIV-1 epidemic. Mathematical modeling may be useful to define how to best use HSV-2 suppression to impact the HIV-1 epidemic by quantifying the benefits, costs, and potential impact of implementing HSV-2 suppression or other non-ART strategies compared to earlier ART initiation to delay HIV-1 disease progression.
Comparison of biomedical clinical trials of non-ART interventions to reduce HIV-1 disease progression
One limitation to this study was the low frequency of diagnostic testing and autopsies to inform the etiology of deaths. Furthermore, although most participants initiated ART at CD4 counts ≥200 cells/mm3
, reasons for ART initiation at higher CD4 counts were not captured since ART care was commonly provided outside the study clinics. TMP-SMX prophylaxis data was also not collected at all sites; however, at five sites where this information was recorded, participants reported TMP-SMX use at 73% of follow-up visits and this did not differ by treatment arm (data not shown). Finally, although studies suggest HIV-1 disease progression may differ by HIV-1 subtype,(48
) subtype data are not currently available for our cohort and will be evaluated in future analyses.
In summary, we have demonstrated that acyclovir for HSV-2 suppression among HIV-1/HSV-2 dually-infected persons with CD4 >250 cells/mm3 who are not taking ART can modestly reduce the risk of HIV-1 disease progression. Further study is needed to determine if HSV-2 suppression has a role in HIV-1 treatment for persons not eligible for ART.